Roell Wilhelm, Lewalter Thorsten, Sasse Philipp, Tallini Yvonne N, Choi Bum-Rak, Breitbach Martin, Doran Robert, Becher Ulrich M, Hwang Seong-Min, Bostani Toktam, von Maltzahn Julia, Hofmann Andreas, Reining Shaun, Eiberger Britta, Gabris Bethann, Pfeifer Alexander, Welz Armin, Willecke Klaus, Salama Guy, Schrickel Jan W, Kotlikoff Michael I, Fleischmann Bernd K
Institute of Physiology I, Life and Brain Center, University of Bonn, Bonn 53105, Germany.
Nature. 2007 Dec 6;450(7171):819-24. doi: 10.1038/nature06321.
Ventricular tachyarrhythmias are the main cause of sudden death in patients after myocardial infarction. Here we show that transplantation of embryonic cardiomyocytes (eCMs) in myocardial infarcts protects against the induction of ventricular tachycardia (VT) in mice. Engraftment of eCMs, but not skeletal myoblasts (SMs), bone marrow cells or cardiac myofibroblasts, markedly decreased the incidence of VT induced by in vivo pacing. eCM engraftment results in improved electrical coupling between the surrounding myocardium and the infarct region, and Ca2+ signals from engrafted eCMs expressing a genetically encoded Ca2+ indicator could be entrained during sinoatrial cardiac activation in vivo. eCM grafts also increased conduction velocity and decreased the incidence of conduction block within the infarct. VT protection is critically dependent on expression of the gap-junction protein connexin 43 (Cx43; also known as Gja1): SMs genetically engineered to express Cx43 conferred a similar protection to that of eCMs against induced VT. Thus, engraftment of Cx43-expressing myocytes has the potential to reduce life-threatening post-infarct arrhythmias through the augmentation of intercellular coupling, suggesting autologous strategies for cardiac cell-based therapy.
室性快速心律失常是心肌梗死后患者猝死的主要原因。在此我们表明，在心肌梗死灶中移植胚胎心肌细胞（eCMs）可预防小鼠室性心动过速（VT）的诱发。移植eCMs而非骨骼肌成肌细胞（SMs）、骨髓细胞或心脏肌成纤维细胞，可显著降低体内起搏诱发的VT发生率。eCMs的植入改善了梗死灶周围心肌与梗死区域之间的电偶联，并且在体内窦房结心脏激活过程中，表达基因编码钙指示剂的植入eCMs发出的Ca2+信号能够被带动。eCMs移植还增加了梗死灶内的传导速度并降低了传导阻滞的发生率。VT的预防关键取决于缝隙连接蛋白连接蛋白43（Cx43，也称为Gja1）的表达：经过基因工程改造以表达Cx43的SMs对诱发的VT提供了与eCMs类似的保护。因此，植入表达Cx43的心肌细胞有可能通过增强细胞间偶联来减少危及生命的梗死后心律失常，这为基于心脏细胞的自体治疗策略提供了思路。
